Genetic Risk Factor For Suicidal Behavior

描述（由申请方提供）：本提案旨在鉴定和表征导致自杀行为易感性的新型基因变异。我们将通过对一个强烈相关的染色体区域进行深入的随访，并通过首次在外显子组范围内搜索与该表型相关的罕见变异来实现这一目标。虽然自杀可能是精神疾病中最可怕的一面，但对其生物学基础的研究相对较少。然而，家庭、双胞胎和收养研究表明，自杀行为有很大的遗传因素。虽然有证据表明，这种遗传性部分是由情绪障碍的倾向，其他证据表明，一个独立的遗传方面，可能跨越多种精神疾病。这种独立的特征被假设为是攻击性和冲动性的一种倾向，其遗传学研究主要集中在多巴胺能基因上。然而，很少有系统的遗传研究自杀倾向的表型已经进行。在该资助的第一次迭代中，我们进行了一项自杀未遂全基因组关联研究（GWAS），该研究在2 p25的rs300774处产生了关联信号（p=5.07 X 10-8），这一发现处于全基因组意义的阈值（p<5X 10 -8）。2 p25上的相关SNP落在包含ACP 1基因的大连锁不平衡块中，ACP 1基因的表达在已完成自杀的双相情感障碍（BP）受试者中显著升高。此外，ACP 1蛋白是与β-连环蛋白相互作用的酪氨酸磷酸酶。与Wnt信号通路中的关键分子β-连环蛋白的联系值得注意，因为Wnt通路受到锂的正调控，锂已被证明可以减少自杀行为。自杀行为和β-连环蛋白之间的联系得到了我们对自杀未遂GWAS数据集的基因集富集分析以及我们对39个BP突变体和60个BP非突变体的初始全外显子组测序的进一步支持。我们建议通过对2 p25候选区域进行重新测序并对800个突变体和1,200个非突变体的全外显子组数据进行二次分析来跟踪这些发现，使我们能够在2 p25、Wnt相关基因和整个基因组中寻找影响自杀行为风险的功能变体。为了实现这一目标，我们将聘请一个优秀的研究团队，包括分子遗传学，统计遗传学，生物信息学，神经生物学和精神病理学专家的多样化和互补的技能。与自杀行为相关的候选基因和功能变体的鉴定将对公共卫生产生重大影响，因为它将为自杀行为的生物学基础提供新的见解，提供新的治疗靶点，并提供生成体内模型所需的数据，以测试治疗靶点。

DESCRIPTION (provided by applicant): This proposal aims to identify and characterize novel gene variants conferring susceptibility to suicidal behavior. We will do this both through intensive follow-up of a strongly implicated chromosomal region, and through performing the first ever exome-wide search for rare variants related to this phenotype. While suicidality is perhaps the most dreaded aspect of psychiatric disorders, relatively little research has been devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. This independent feature has been hypothesized to be a liability to aggressiveness and impulsivity, the genetic study of which has focused on serotonergic genes. However, little systematic genetic investigation of the suicidality phenotype has been undertaken. In the first iteration of this grant, we conducted an attempted suicide genome-wide association study (GWAS), which generated an association signal on 2p25 at rs300774 (p=5.07 X 10-8), a finding that is on the threshold of genome-wide significance (p<5X10-8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block that contains the ACP1 gene, whose expression is significantly elevated in bipolar disorder (BP) subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that interacts with beta-catenin. The connection to beta-catenin, a key molecule in the Wnt signaling pathway, is noteworthy because the Wnt pathway is positively regulated by lithium, which has been shown to decrease suicidal behavior. The connection between suicidal behavior and beta-catenin was further supported by our gene set enrichment analysis of our attempted suicide GWAS dataset and by our initial whole-exome sequencing of 39 BP attempters and 60 BP non- attempters. We propose to follow up these findings by resequencing the 2p25 candidate region and by conducting a secondary analysis of whole-exome data from 800 attempters and 1,200 non-attempters, allowing us to search for functional variants influencing the risk for suicidal behavior on 2p25, in Wnt-related genes, and throughout the genome. To accomplish this, we will employ the diverse and complementary skill sets of an outstanding team of investigators including experts in molecular genetics, statistical genetics, bioinformatics, neurobiology, and psychopathology. The identification of candidate genes and functional variants associated with suicidal behavior would have a significant public health impact because it would provide new insights into the biological basis of suicidal behavior, provide new therapeutic targets, and provide the data needed to generate in vivo models in which to test therapeutic targets.